Project Summary. The demands of modern society, career pressures, and technological advances in personal electronics and communication have increased sleep deprivation and sleep disorders across age groups. Sleep deprivation adversely impacts individual health with increased disease incidence and decreased cognitive function resulting in increased medical care, as well as occupational and traffic accidents. The negative impact of sleep deprivation on memory can be observed across species suggesting that the sleep deprivation may alter highly conserved molecular and cellular mechanisms to impact memory. The hippocampus is an excellent model to investigate the neural impacts of sleep deprivation as hippocampal activity is necessary for spatial memory and this type of memory is particularly susceptible to sleep deprivation. Current evidence indicates that sleep loss impairs the formation and stability of memories at the cellular level through changes in the synapses of individual neurons. However, the specific basis of how sleep deprivation adversely affects memory and how the brain can be rendered resilient to these effects remains poorly understood. It is critical to define the cellular, molecular and network mechanisms through which sleep deprivation impacts neural function given not only the rising incidence of sleep deprivation but also the aggravating impact of sleep loss on many neuropsychiatric, neurological and neurodegenerative disorders. Our previous research has identified decreased second messenger signaling, suppression of protein synthesis and changes in neuron dendritic structure as pathways through which sleep deprivation affects memory. However, it remains unknown if sleep deprivation separately impacts targets in each of these pathways or if the effects of sleep deprivation are mediated through a central molecular node. The objective of this proposal is to identify the molecular and neuronal mechanisms through which sleep loss impairs synaptic plasticity and memory formation by focusing on the molecular, cellular and network mechanisms through which resilience to sleep deprivation can occur. In Specific Aim 1, we use a novel transgenic approach we developed to spatially and temporally manipulate a second messenger signaling pathway. This will allow us to investigate the molecular mechanisms which underlie neuronal resilience to the detrimental effects of sleep loss. In Specific Aim 2, we investigate several types of hippocampal synaptic plasticity targeted by sleep deprivation at the neuronal level to identify which is associated with resilience. In Specific Aim 3, we identify the network and circuit properties of neurons affected by sleep deprivation using in vivo recordings from large neuronal populations. The results from our comprehensive experimental approach at the behavioral, biochemical, molecular, and electrophysiological levels will provide significant insights into the molecular signature that promotes resilience to the negative impact of sleep deprivation on memory. As such, our work may potentially lead to the development of interventions to overcome the detrimental effects of sleep deprivation on cognition.